The objective of this proposal is to identify antibodies which might represent correlated of protective immunity in HIV-1. It is possible that in depth studies of long term survivors of HIV-1 infection who manifest unusually strong parameters of antiviral immunity will provide information on which immune responses are protective. Our goal will be to isolate and characterize human monoclonal antibodies from a cohort of long-term survivors of HIV infection whose sera contain broad and potent serum neutralizing antibodies against primary HIV-1 isolates. Antibodies will also be derived from a subset of HIV-1 seroconverter patients who produce equally effective neutralizing antibodies to primary viruses. An underlying hypothesis is that an analysis of the total group of HMAbs derived from these subjects will reveal what kinds of antibodies account for neutralization of primary HIV-1 isolates. We believe that this approach lead to a better understanding of the correlates of protective immunity to HIV infection. We have developed new antibody screening methods which efficiently detect antibodies to envelope glycoproteins from autologous and heterologous primary isolates. In addition, a major effort will be directed toward the development of assays which will detect antibodies reacting with oligomeric envelope glycoproteins of primary viruses, since certain neutralization epitopes may be preferentially or uniquely exposed on oligomeric envelope structures on infectious virions. This type of antibody might be missed if we rely solely on assays utilizing solubilized monomeric glycoproteins. We will test all monoclonal antibodies that we isolate for virus neutralization and characterize their epitopes.